title: Succinyl hydroxamates as potent and selective non-peptidic inhibitors of procollagen C-proteinase: design, synthesis, and evaluation as topically applied, dermal anti-scarring agents.
abstract: Succinyl hydroxamates 1 and 2 are disclosed as novel series of potent and selective inhibitors of procollagen C-proteinase (PCP) which may have potential as anti-fibrotic agents. Carboxamide 7 demonstrated good PCP inhibition and had excellent selectivity over MMPs involved in wound healing. In addition, 7 was effective in a cell-based model of collagen deposition (fibroplasia model) and was very effective at penetrating human skin in vitro. Compound 7 (UK-383,367) was selected as a candidate for evaluation in clinical studies as a topically applied, dermal anti-scarring agent.
authors.affiliation: Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. simon.bailey@pfizer.com
authors.forename: Simon
authors.initials: S
authors.lastname: Bailey
authors.forename: Paul V
authors.initials: PV
authors.lastname: Fish
authors.forename: Stephane
authors.initials: S
authors.lastname: Billotte
authors.forename: Jon
authors.initials: J
authors.lastname: Bordner
authors.forename: Doris
authors.initials: D
authors.lastname: Greiling
authors.forename: Kim
authors.initials: K
authors.lastname: James
authors.forename: Andrew
authors.initials: A
authors.lastname: McElroy
authors.forename: James E
authors.initials: JE
authors.lastname: Mills
authors.forename: Charlotte
authors.initials: C
authors.lastname: Reed
authors.forename: Robert
authors.initials: R
authors.lastname: Webster
mesh_terms: D000279:Administration, Cutaneous; D055395:Bone Morphogenetic Protein 1 / Q000737:chemistry*; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002921:Cicatrix / Q000188:drug therapy*; D017439:Cicatrix, Hypertrophic / Q000188:drug therapy*; D015195:Drug Design; D004817:Epidermis / Q000187:drug effects; D005355:Fibrosis / Q000473:pathology; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D010080:Oxazoles / Q000737:chemistry
chemical_list: D006877:Hydroxamic Acids; D010080:Oxazoles; C525705:BMP1 protein, human; D055395:Bone Morphogenetic Protein 1